Field of the Disclosure
This disclosure relates to methods of reducing adverse consequences of myocardial infarction.
Description of the Related Art
The problems and health consequences of heart disease are far reaching. Heart disease is the leading cause of death for both women and men in the United States. (Kung H C, Hoyert D L, Xu J, Murphy S L. Deaths: final data for 2005. National Vital Statistics Reports. 2008; 56(10)). Every 34 seconds a person in the United States dies from heart disease. More than 2,500 Americans die from heart disease each day. In 2005, 652,091 people died of heart disease (50.5% of them women). This was 27.1% of all U.S. deaths. Heart disease is the leading cause of death for American Indians and Alaska Natives, blacks, Hispanics, and whites. For Asians and Pacific Islanders, cancer is the leading cause of death (accounting for 27.5% of all deaths), heart disease is a close second (25.0%). (CDC. Deaths: leading causes for 2004. National Vital Statistics Reports. 2007; 56(5)). Almost 6 million hospitalizations each year (in the United States) are due to cardiovascular disease.
In 2009, heart disease is projected to cost more than $304.6 billion, including health care services, medications, and lost productivity. (American Heart Association. Heart Disease and Stroke Statistics—2009 Update. Dallas; AHA: 2009. Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008 Dec. 15.) Worldwide, coronary heart disease killed more than 7.6 million people in 2005. (World Health Organization. The Global Burden of Disease: 2004 Update. Geneva; WHO: 2008.) In 2003, approximately 37% of adults reported having two or more of six risk factors for heart disease and stroke (high blood pressure, high cholesterol, diabetes, current smoking, physical inactivity, and obesity). (Hayes D K, et al., Disparities in multiple risk factors for heart disease and stroke, 2003 MMW., 2005; 54:113-116).
Myocardial infarction (MI) is cardiac tissue death caused by ischemia. “Ischemia” refers to local deficiency of blood supply, generally produced by vasoconstriction or local obstacles to blood flow. Restoration of blood flow to a previously ischemic tissue or organ, such as the heart is referred to as “reperfusion.”
Acute myocardial infarction (AMI), or a “heart attack,” occurs when localized myocardial ischemia causes the development of a defined region of tissue death. AMI is most often caused by rupture of an atherosclerotic lesion in a coronary artery. This causes the formation of a thrombus that plugs the artery, stopping it from supplying blood to the region of the heart that it supplies.
Severe and prolonged ischemia produces a region of necrosis spanning the entire thickness of the myocardial wall. Such a transmural infarct usually causes ST segment elevation. Less severe and protracted ischemia can arise when coronary occlusion is followed by spontaneous reperfusion; an infarct-related artery is not completely occluded; occlusion is complete, but an existing collateral blood supply prevents complete ischemia; or the oxygen demand in the affected zone of myocardium is smaller. Under these conditions, the necrotic zone may be mainly limited to the subendocardium, typically causing non-ST segment elevation MI.
Both infarcted and unaffected myocardial regions undergo progressive changes over the hours, days and weeks following an ischemic event. This process of postinfarct myocardial evolution leads to the occurrence of characteristic changes at predictable times after the initial event. Acute ischemia causes an immediate loss of contractility in the affected myocardium, a condition termed hypokinesis. Necrosis starts to develop in the subendocardium about 15-30 min after onset of acute ischemia. The necrotic region grows outward towards the epicardium over the next 3-6 h, eventually spanning the entire ventricular wall. At the edges of the infarct, the myocardium may be stunned (reversibly damaged) and will eventually recover if bloodflow is restored. Contractility in the remaining viable myocardium increases, a process termed hyperkinesis.
A progression of cellular, histological and gross changes develop within the infarct. Alterations in the gross appearance of infarcted tissue are not apparent for at least 6 h after the onset of cell death. However, cell biochemistry and ultrastructure begin to show abnormalities within 20 min. Cell damage is progressive, becomingly increasingly irreversible over about 12 h.
Between 4 and 12 h after cell death starts, the infarcted myocardium begins to undergo coagulation necrosis, a process characterized by cell swelling, organelle breakdown and protein denaturation. After about 18 h, neutrophils (phagocytic lymphocytes) enter the infarct. Their numbers reach a peak after about 5 days, and then decline. After 3-4 days, granulation tissue appears at the edges of the infarct zone. This consists of macrophages, fibroblasts (which lay down scar tissue), and new capillaries. The infarcted myocardium is especially soft between 4 and 7 days, and is therefore maximally prone to rupturing. As the granulation tissue migrates inward toward the centre of the infarct over several weeks, the necrotic tissue is engulfed and digested by the macrophages. The granulation tissue then progressively matures, with an increase in connective (scar) tissue and loss of capillaries. After 2-3 months, the infarct has healed, leaving a noncontracting region of the ventricular wall that is thinned, firm and pale grey.
Microscopic morphologic changes evolve over time as follows: Wavy myocardial fibers appear 1-3 hours after onset of ischemia. A staining defect with tetrazolium or basic fuchsin dye appears 2-3 hours after onset of ischemia. Coagulation necrosis with loss of cross striations, contraction bands, edema, hemorrhage, and early neutrophilic infiltrate appear 4-12 hours after onset of ischemia. Continuing coagulation necrosis, pyknosis of nuclei, and marginal contraction bands are apparent 18-24 hours after onset of ischemia. Total loss of nuclei and striations along with heavy neutrophilic infiltrate appears 24-72 hours after onset of ischemia. Macrophage and mononuclear infiltration, and, fibrovascular response begin 3-7 days after onset of ischemia. A fibrovascular response with prominent granulation tissue is apparent 10-21 days after onset of ischemia. Fibrosis is readily apparent 7 weeks or sooner after an ischemic event.
Complications can include: arrhythmias and conduction defects, extension of infarction or re-infarction, congestive heart failure, cardiogenic shock, pericarditis, mural thrombosis with possible embolization, myocardial wall rupture with possible tamponade, papillary muscle rupture with possible valvular insufficiency, and ventricular aneurysm formation.